Neuronal activation in the axolotl brain promotes spinal cord regeneration

The axolotl retains a remarkable capacity for regenerative repair and is one of the few vertebrate species capable of regenerating its brain and spinal cord after injury. To date, studies investigating axolotl spinal cord regeneration have placed particular emphasis on understanding how cells immediately adjacent to the injury site respond to damage to promote regenerative repair. How neurons outside of this immediate injury site respond to an injury remains unknown. Here, we identify a population of dpErk ⁺ /etv1 ⁺ glutamatergic neurons in the axolotl telencephalon that are activated in response to tail amputation. Importantly, the activation of these neurons facilitates successful tail regeneration by promoting axon extension into the newly regenerated tissue. We demonstrate that these dpErk ⁺ neurons extend axons into the hypothalamus, which has a well-established role in hormone production. Furthermore, these neurons upregulate the neuropeptide neurotensin in response to injury, which in turn stimulates the production of multiple hormones in the hypothalamus to promote regenerative repair. Together, these findings identify a unique population of neurons in the axolotl brain whose activation is necessary for successful spinal cord regeneration, and sheds light on how neurons outside of the immediate injury site respond to a spinal cord injury.